Malaria is a debilitating disease. It triggers periodic flu-like attacks with headaches, chills and severe fevers that can last for 48 to 72 hours.

It is caused by Plasmodium parasites that are spread from human to human through bites from infected mosquitoes.

If not treated with anti-malarial drugs, the disease is often fatal. Today in Africa, malaria is responsible for one in every five childhood deaths.

Areas where malaria is endemic (there is some level of malarial infection maintained within the population) are coloured yellow. Diagram: CDC Division of Parasitic Diseases.

Plasmodium parasites use human red blood cells, which contain large quantities of haemoglobin, as food sources.

Haemoglobin is a protein used in the body for oxygen transport. If there is not enough haemoglobin (which contains iron), parts of the body will not receive adequate oxygen to keep the cells in the body producing energy.

This results in anaemia (low iron levels), causing fatigue and other symptoms.

Diagram: Based on work by National Human Genome Research Institute (US)

Interestingly, many people who live in areas where malaria is prevalent have developed resistance to the Plasmodium parasite. This appears to be linked to the genetically shaped-altered haemoglobin (sickle-like shapes, as opposed to the usual spheres).

How was malaria originally treated?

The first significant drug for malaria was quinine, a bitter-tasting white powder that comes from the bark of the cinchona tree. This tree is found in the Andes mountain ranges of Ecuador and Peru.

Quinine was introduced to Europe in the mid-seventeenth century and demand for quinine resulted in most cinchona trees being cut down.

A steady supply of quinine was re-established in the 20th century, when a chemical method of making quinine from coal tar was introduced.

The Cl (Chlorine) and Fe (Iron) parts of chloroquine and ferroquine are thought to be used to get the active quinine part of the drug close enough to kill Plasmodium parasites; they are important for drug delivery.

Before discussing any one disease or family of drugs in much depth, it’s worth having a look at the method used by pharmaceutical companies to develop drugs.

Mankind has been using plants extracts as medicine for a long time.

During the mid 19th century, people started trying to isolate the active compounds within these plants- the molecules responsible for the medicinal qualities.

This was the beginning of the pharmaceutical industry.

Picture: Clip Art

Drug Companies work on the basis of expected return for their investment. So, sadly, when they identify a disease to try to cure, it is not usually going to be a disease attacking the developing world where people do not have much money.

When you have a look at the rate of success in drug development, the reasons behind this mercenary attitude become a little clearer:

For every 10 000 molecules investigated for possible medicinal qualities, only 10 reach clinical trials and only 1 of those may be made available for patients.

The average overall development cost for a new drug is estimated to be over NZ$800 million at current exchange rates (GBP £444 million).

Average time to develop a drug is 10-15 years

Once a disease has been chosen, the next step is to identify a suitable drug target. This is where it is very important to understand how the disease works and what is going on in the body.

Typically, a drug target is one of the following three parts of the body that is involved in the disease.

Receptor (a protein on a cell surface, allows chemical messengers into the cell)

Enzyme (act as catalysts to make biological reactions happen easier)

Nucleic acid (part of DNA)

Thousands of molecules are then screened to choose a lead compound. This is a molecule that interacts with the drug target in a therapeutic way to help control the disease.

Chemistry comes to the fore now as lots of variations of this lead compound are made. These different compounds are then analysed to discover which will control the target disease safely.

Having discovered the best compound to act as your drug, the next step is to make sure the drug will reach its target in the body.

Drugs need to be absorbed into the blood, to reach their target efficiently, to be stable enough to survive the journey, and to be excreted within a reasonable length of time.

Again, chemistry is used to manipulate the properties of the chosen compound to get this to happen.

Before this drug hits the market, there are still many different issues to deal with:

patents,

pre-clinical trials,

three stages of clinical trials

on-going studies to monitor the long-term effects of this drug

registration and approval from the Food and Drug Administation in the United States.

Drug Development: An Example

Identified disease: Asthma.

Disease background:Asthma is when lung bronchi (airways) become narrower. When faced with certain triggers, these airways may partially close up, swell or make more mucous and become clogged up.

This can cause difficulty in breathing, a feeling of tightness in the chest, coughing and wheezing. Severe asthma can cause death.

Diagram: United States Federal Government (Wikipedia Commons)

Chosen drug target: Beta-2 Adrenoreceptor.

There are several different types of receptors in the body that are activated or ‘turned on’ by a molecule of adrenaline reaching them.

Adrenaline activates Beta-2 receptors. This causes smooth muscles to relax. Relaxing the smooth muscles in the bronchi will widen the airways, which helps a person suffering from asthma to breathe easier.

Lead compound: Adrenaline.

Adrenaline itself was one of the first compounds used to help in asthma attacks.

It produces short-term relaxation of the airways but it also stimulates a lot of other types of adrenergic receptors, leading to many side-effects including heart problems.

Developed drug compound: Salbutamol (trade name Ventolin).

Salbutamol is over 2000 times less active on the heart than adrenaline, meaning it produces fewer side effects.

The relaxing effect of Salbutamol on the smooth muscle of the bronchi lasts for 4 hours.

Interestingly, Salbutamol is a chiral compound, meaning that it is two non-superimposable mirror images.

For a simple example of chiral objects hold your hands out, palms facing away from you. Your hands are mirror images of each other. Try to get your hands to look exactly the same, top and bottom of the hands facing the same way and thumbs on the same side. It’s not possible: your hands are non-superimposable mirror images.

Both of these mirror image compounds (called R and S to distinguish them) were produced in the Salbutamol drug until it was recognised that the R-compound is 68 times more active than the S-compound.

The less-active S-compound is also the one held responsible for side effects. This resulted in production of pure R-salbutamol, called Levalbutarol (trade name Xopenex).

To summarise, the process of drug development process requires investment of a phenomenal sum of time and money. Return on investment currently holds great influence over which disease is chosen to design drugs for. The desperate need seen in developing countries for drugs to tackle tuberculosis (TB), malaria, sleeping sickness and other tropical diseases is largely ignored.

So, we now have some idea of how the eye works and the role of Vitamin A in sight. Colour blindness is only one of the problems that may occur in the eye, one that has no real solution. So what are some of the solvable eye problems?

Conjuctivitis (cornea)

Picture: Ansevilu

This is also known as ‘pink eye’ and is the result of irritation of the clear membrane covering the white part of the eye and interior of the eyelid. There are three general causes:

Allergies

Bacterial Infection

Viral Infection

Viral conjunctivitis usually clears up within a few weeks, while anti-biotic eye drops are used to kill off bacterial infections in the eye. Artificial tears are often used to help prevent the symptoms of allergic conjunctivitis, as they help to dilute any dust or foreign allergy-causing substance in your eye. Anti-histamine pills can also help to control conjunctivitis.

Short- or Long-Sightedness

Myopia, or short-sightedness, is an eye condition where distant objects appear blurry because light rays are focused to a point in front of the retina.

Hyperopia, or long-sightedness, is the corresponding eye condition that makes close objects appear blurry because light rays are focused behind the retina.

These conditions are caused either because the cornea is too curved or flat, respectively, or by an unusually shaped eyeball.

Traditional methods of dealing with short- and long-sightedness include glasses and contact lenses.

In the case of short-sightedness, a concave lens in the glasses is used to move the point where the light converges from the middle of the eye to the retina.

In long-sightedness, a convex lens is used to move the focus point of light forward onto the retina rather than behind the eye.

Specially trained eye surgeons are now able to use laser technology to re-shape the cornea of the eye. This removes the need for corrective glasses or contact lenses.

For further information about correcting short- or long-sightedness, see

A cataract is when the lens of the eye becomes cloudy. A cloudy lens prevents light from going through the lens to the retina and so blindness ultimately results.

According to the World Health Organisation cataracts are the leading cause of blindness, being responsible for 48% of blindness in the world.

Most cataracts are caused by aging. Because the lens in the eye is made up of mainly protein and water, as it ages the carefully-arranged proteins can clump together, clouding the lens.

Occasionally children are born with a cataract or one may develop after eye injury, inflammation or some other eye disease.

Cataracts are treated by surgery to remove the clouded lens and replace it with a synthetic one. This synthetic lens can be concave or convex in order to fix short- or long-sightedness at the same time as restoring sight.

Understanding better how the eye works, from both a biological and chemical perspective, has led to important discoveries about how to improve night vision and prevent blindness.

Eye conditions such as conjunctivitis, short-and long-sightednesss and cataracts can be successfully treated using a variety of methods. Vitamin A is now deliberately added to food while lens and laser surgery are restoring sight.

Retinal, one of the parts of rhodopsin, is a special form of Vitamin A. One of the sources of Vitamin A in our diet is carrots so there is a strong belief that eating carrots will help you see better in the dark.

Retinal is essential for the functioning of the eye, in particular the rods in the eye. Rods provide black and white vision and respond in dim light, while cones provide colour vision and respond to bright light.

During the day, the incoming light is strong enough that what little retinal is around will be activated to start the process of vision. At night, when there is a lack of retinal, it becomes difficult for the rods to sense the small amount of light around and this results in poor night vision.

Geneticist Phillip Simon and horticulturalist Clinton Peters at the University of Wisconsin have developed a new variety of carrot called the Beta III. This ‘supercarrot’ contains three to five times the concentration of Vitamin A in normal carrots. This Beta III carrot is designed to combat the blindness caused in developing countries by a lack of Vitamin A.

“Worldwide each year Vitamin A deficiency causes 10 million cases of night blindness and one million cases of cloudy vision.” Dr Phillip Simon.

However, lack of Vitamin A in your diet not only affects night vision, but can cause poor immune responses and has been linked to anaemia.

Good sources of Vitamin A include green leafy plants, yellow fruits such as golden mangoes, palm oils and of course carrots. Other foods that have been artificially fortified with Vitamin A include margarine, wheat, rice, edible oils, and sugar.

Interestingly, eating large amounts of carrots will only improve your eyesight if you don’t already have enough Vitamin A in your diet. A professor at Melbourne University in Australia has this to say about the carrot myth:

“No amount of carrots will improve your eyesight if you already have a well-balanced diet.” Professor Algis Vingrys of Melbourne University

We all have some understanding of the importance of the eye. We rely on sight every day. Studying the eye can help us understand the basis of eye problems such as conjunctivitis, colour blindness, and cataracts. It’s a fascinating topic to learn more about.

How our eyes work

Diagram: Ruth Lawson

Light enters the eye through the pupil (part of the iris) and is focused onto the fovea (focal point) through a combination effort between the cornea and the lens.

The cornea acts as an ‘outer lens’ and bends incoming light onto the lens. The lens then refocuses this light onto the first layer of cells in the retina as an upside-down image.

Cells in the retina convert the light into a series of electrical impulses that are sent via the optic nerve to the brain. The brain adds all these impulses signals together to re-form the upside-down image and makes sense of it by turning it up the right way.

Focus on Chemistry

Chemistry is a crucial part of the third step, where the retinal image is broken down into neural signals that are sent to the brain.

The retina is made up of several layers of cells: a layer of ganglion cells (which make up the optic nerve), a layer of neural cells and a layer of rods and cones.

Light must first travel to the rods and cones at the back of the retina, where some really interesting chemistry takes place to break the image into electrical impulses. These impulses are then transmitted to the neural cells, then to the optic nerve and the brain. This process is called phototransduction.

Chemistry in Rods and Cones

Picture: Wikipedia Commons

There are some 120 million rods and 6 million cones in the retina. Rods are responsible for night vision, sensitive motion detection and peripheral vision. Cones are responsible for colour vision.

A light sensitive pigment called rhodopsin is found in the rods and cones.

Rhodopsin is made up of one of several types of opsin proteins and a small molecule called retinal, chemically bound together. The different types of opsin proteins are designed to detect, among other things, different wavelengths of light and so allow us to see in colour.

Chemistry in the Retina

Light hitting a molecule of rhodopsin causes isomerisation (a change in shape) of the pigment as it gains energy.

This energy-rich rhodopsin molecule then transfers energy to neural cells, which causes them to start an electrical impulse that travels along the optic nerve to the brain to paint a very small part of a large picture.

This process occurs in the millions of rod and cone cells in the retina, resulting in information about an overall image being sent to the brain.

Meanwhile, the excited rhodopsin molecule has lost its extra energy and splits into its two parts of opsin and chemically changed retinal. A complicated chemical process then regenerates the original retinal molecule and joins it back to the opsin protein to make rhodopsin again.

Have you ever heard that a little bit of knowledge is a dangerous thing? When we look at the history of treating stomach peptic ulcers, the importance of thoroughly understanding a medical condition in order to treat it effectively becomes obvious.

So, what is a peptic ulcer?

It’s a hole in the mucous membrane of the stomach. This hole allows the gastric acid in your stomach to reach the stomach lining, irritating it and causing dull or burning pain*. If left untreated, peptic ulcers can result in severe bleeding and even death. However, there have been effective treatments around for ulcers since the 1970’s.

When pharmaceutical companies first looked at developing medicines for treating stomach ulcers, they were thought to be caused by stress, spicy food or alcohol. Nowadays, we know otherwise, but these factors can make the symptoms of a peptic ulcer worse.

It was understood then, and still is today, that gastric acid makes peptic ulcers worse. So the first type of medication developed for treating peptic ulcers were H2 Histamine antagonists.

Histamine, a hormone, can cause the release of gastric acid from parietal cells in the stomach. This happens when histamine interacts with a special type of receptor on these cells called the H2 receptor. H2 Histamine antagonists such as cimetidine (trade name Tagamet) bind to H2 receptors without stimulating gastric acid release, blocking Histamine from binding and so decreasing the amount of gastric acid produced in the stomach.

Cimetidine, marketed in the UK in 1976, was the first really effective antiulcer drug. No longer was it necessary to swallow large amounts of antacids (bases such as sodium bicarbonate or calcium carbonate) to try to neutralize gastric acid. No longer was surgery the only way to get rid of a peptic ulcer.

As effective as drugs like cimetidine were, a new and superior class of medication to treat ulcers was developed in the 1980’s. These new drugs are called Proton Pump Inhibitors (PPI’s).

All gastric acid production is done in the parietal cells through an enzyme complex called a proton pump. A Proton Pump Inhibitor such as omeprazole (trade name Losec) is a weak base. When it reaches the highly acidic openings to the parietal cells, it is ionized to an active form and binds irreversibly to the proton pump by forming a covalent bond to a free Histidine residue. This prevents formation of hydrochloric acid, the main component of gastric acid.

Drugs like cimetidine prevent histamine from stimulating the proton pump to produce hydrochloric acid, blocking one stimulatory pathway. But there are other ways to activate the proton pump. Drugs like omeprazole prevent the proton pump from producing any hydrochloric acid. This is clearly a better way to reduce the amount of gastric acid in the stomach near a peptic ulcer.

However, one of the puzzling aspects of stomach ulcers is their tendency to reoccur after finishing a course of medication.

This was explained to be because of a microorganism called H. pylori in the stomach. Scientific evidence has implicated H. pylori infection as one of the main causes of peptic ulcers. H. pylori are associated with inflammation of the stomach, as they can produce cytotoxins that have been specifically linked to peptic ulceration**.

Treatment of H. pylori infection is done using antibiotics. Combination therapy of a PPI and at least two bacterial agents has been shown to eradicate H. pylori in over 90% of ulcers and significantly reduce the likelihood of reoccurrence of a peptic ulcer***.

So from an approach aimed at preventing aggravation of an ulcer by reducing the amount of gastric acid in the stomach, medicine is now trying to kill off one of the main cause of ulcers: H. pylori.

It is worth mentioning briefly that the other main cause of ulcers is non-steroidal anti-inflammatories (NSAIDS) such as asprin. NSAIDS prevent a special enzyme called COX-1 from working. This enzyme produces a chemical messenger to stop acid secretion and protect the walls of the stomach.

Please note: This information is not designed to help anyone make self-diagnoses. There is a reason our doctors train for at least 6 years before they are allowed to practice medicine. The human body is wonderfully made and a complex biological environment. Stomach pain can be an indicator of many different medical problems.

I guess I see chemistry as being a crucial part of medicine in two ways.

Chemistry is what I call the ‘how’ and ‘why’ part of science. Biology can tell us a lot about what is involved in biological systems, but when we look at the human body in terms of wanting to cure disease, we need to understand:

How the body works normally, so we can see what may have gone wrong.

Chemistry is involved in modelling chemical systems in the body, to increase our understanding of how we work. For example, the way haemoglobin (a protein that stores iron) takes up and releases iron in the body has been studied* and found to work using chemical oxidation and reduction processes.

Why something may have gone wrong, and how we might be able to fix it.

What might have gone wrong: Chemists have developed useful diagnostic tools used everyday in hospitals, such as Magnetic Resonance Imaging (MRI) and CT scanning. These techniques allow pictures (using magnetic waves or x-rays) to be taken so doctors can see the organs, bones and tissue inside a patient.

Trying to fix it: Chemistry also plays a huge role in the development of synthetic drugs such as antibiotics, antimalarials and analgesics (pain killers). New research is being done on possible ways chemistry can be used to target cancer cells without killing the healthy cells around the cancer growths.